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This systematic review aimed to explore the relationship between diabetic peripheral neuropathy (DPN) and cardiac autonomic neuropathy (CAN) in individuals with type 1 and 2 diabetes mellitus (DM). METHODS: The systematic review follow the protocol registered in Prospero (CRD42020182899). Two authors independently searched the PubMed, Scopus, Embase, Cochrane, and Web of Science databases. Discrepancies were resolved by a third author. The review included observational studies investigating the relationship between CAN and DPN in individuals with DM. RESULTS: Initially, out of 1165 studies, only 16 were selected, with 42.8 % involving volunteers with one type of diabetes, 14.3 % with both types of diabetes and 14.3 % not specify the type. The total number of volunteers was 2582, mostly with type 2 DM. It was analyzed that there is a relationship between CAN and DPN. It was observed that more severe levels of DPN are associated with worse outcomes in autonomic tests. Some studies suggested that the techniques for evaluating DPN might serve as risk factors for CAN. CONCLUSION: The review presents a possible relationship between DPN and CAN, such as in their severity.

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OBJECTIVES: Hypermetabolic state in Graves' disease (GD) has a great impact on heart homeostasis, acting directly on the heart muscle and modulating the autonomic nervous system. To characterize cardiac autonomic neuropathy (CAN) as a possible complication in patients with GD. METHODS: We evaluated euthyroid GD patients and a control group of healthy euthyroid people. CAN was assessed using autonomic tests of cardiovascular reflex and heart rate variability: respiratory, Valsalva, orthostatic and orthostatic hypotension tests, high frequency, low frequency, and very low-frequency bands. Transthoracic echocardiography was performed in GD patients. RESULTS: Sixty GD patients and 50 people in control group were assessed. CAN was diagnosed in 20% of GD and 14% in the control group. Among GD, 13.3% presented incipient, and 6.7% established CAN, while in the control group, it was verified incipient in 8% and established in 6% (P = .7479). All GD patients with CAN presented an alteration in the deep breathing test. Age and smoking were evidenced as factors associated with the presence of CAN, while higher TRAb values at diagnosis decreased the chance of CAN. CONCLUSIONS: The prevalence of CAN in euthyroid GD patients was 20%. Changes in the cardiac autonomic nervous system were identified, pointing to the importance of evaluating this complication in these patients. Smoking was a predictive factor for CAN, increasing its relationship with conditions that aggravate GD.

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Resumen La neuropatía autonómica cardiovascular asociada a diabetes es una seria complicación de la diabetes mellitus (DM), que se relaciona con gran carga de morbilidad e incremento significativo de la mortalidad. Tiene un amplio espectro de alteraciones, que van desde taquicardia en reposo, a intolerancia al ejercicio e isquemias silentes. El tratamiento de estas complicaciones es variado, pues intervienen muchos factores tanto en su génesis como en su control, por lo que se han buscado varias estrategias que puedan impactar en su evolución. El ejercicio es considerado como una estrategia de primera línea para el manejo de la DM, así como en la prevención y tratamiento de la neuropatía autonómica cardiovascular, puesto que disminuye su incidencia y evolución en el tiempo. Para prescribir de forma segura y efectiva el ejercicio en pacientes con neuropatía autonómica cardiovascular, los prestadores de servicios de salud deben entender la fisiopatología de la enfermedad, sus manifestaciones clínicas y su comportamiento durante el ejercicio, con lo cual se podrá estructurar un programa individualizado para las necesidades de cada paciente. Se realizó una búsqueda de la literatura en bases de datos (PubMed, MEDLINE, EMBASE, Scopus), con los términos MESH neuropatías diabéticas + diabetes mellitus + terapia por ejercicio, determinando que realizar ejercicio aeróbico de moderada intensidad disminuye la incidencia y progresión de la neuropatía autonómica cardiovascular, favorece el control de síntomas y disminuye el riesgo de mortalidad. Otros tipos de ejercicio, como el entrenamiento de fuerza y el aeróbico intermitente de alta intensidad, también demostraron mejoría, pero la evidencia en cuanto a su uso aun es limitada.

Abstract Diabetic cardiovascular autonomic neuropathy (CAN) is a serious complication of diabetes mellitus, which is associated with a high burden of morbidity and a significant increase in mortality. Cardiovascular autonomic neuropathy can manifest through a wide spectrum of alterations, ranging from resting tachycardia to exercise intolerance, and the presence of silent ischemia. The treatment of this complication varies, as there are many factors involved in both its genesis and control; therefore, various strategies have been sought to affect its course. Exercise is considered a first-line strategy for the management of diabetes mellitus and its usefulness in the prevention and management of CAN has also been proven, reducing its incidence and progression over time. In order to safely and effectively prescribe exercise in patients with CAN, healthcare providers need to understand the pathophysiology of the disease, its clinical manifestations and their behavior during exercise, to be able to structure an individualized program for the patients. A database literature search was carried out in PubMed, MEDLINE, EMBASE, and Scopus using the MESH terms diabetic neuropathies + diabetes mellitus + exercise therapy, where it was determined that performing moderate aerobic exercise decreases the incidence and progression of CAN, favors the control of symptoms and is associated with a decrease mortality risk. Other types of exercise such as strength training and high intensity intermittent training have also shown improvement; nevertheless there is still limited evidence regarding their use.

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Cardiovascular autonomic neuropathy (CAN) is a severe complication of the advance stage of diabetes. More than 50% of diabetic patients diagnosed with peripheral neuropathy will have CAN, with clinical manifestations including tachycardia, severe orthostatic hypotension, syncope, and physical exercise intolerance. Since the prevalence of diabetes is increasing, a concomitant increase in CAN is expected and will reduce quality of life and increase mortality. Autonomic dysfunction is associated with reduced baroreflex sensitivity and impairment of sympathetic and parasympathetic modulation. Various autonomic function tests are used to diagnose CAN, a condition without adequate treatment. It is important to consider the control of glucose level and blood pressure as key factors for preventing CAN progression. However, altered biomarkers of inflammatory and endothelial function, increased purinergic receptor expression, and exacerbated oxidative stress lead to possible targets for the treatment of CAN. The present review describes the molecular alterations seen in CAN, diagnosis, and possible alternative treatments.

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Chronic treatment with sildenafil (SILD) is an effective protector on the development of cardiovascular complications of pulmonary hypertension (PH) and diabetes. However, to date, no studies have evaluated the effect of SILD on cardiopulmonary pathophysiology during PH secondary to type 1 diabetes. AIM: The present study aimed to evaluate the beneficial effects of chronic SILD treatment on pulmonary arterial pressure, right ventricular hypertrophy (RVH) and cardiac autonomic dysfunction in rats with PH secondary to diabetes. METODOLOGY: Male Sprague Dawley rats were randomly distributed into the control group (saline), diabetic group (60 mg/kg with streptozotocin), SILD-treated control group (20 mg/kg) and SILD-treated diabetic group. RESULTS: After 8 weeks the type 1 diabetic animals presented PH, endothelial dysfunction of the pulmonary arteries, electrocardiographic alterations, RVH and overexpression of phosphodiesterase type 5 in the heart. In type 1 diabetic animals, SILD treatment prevented the development of PH, endothelial dysfunction and RVH. SILD treatment also prevented alterations in the corrected QT period and heart rate variability and prevented overexpression of phosphodiesterase type 5. CONCLUSION: Our results indicate for the first time that SILD treatment prevents pulmonary arterial endothelial dysfunction, pulmonary hypertension, right ventricular hypertrophy and improves heart rate variability in type 1 diabetic rats.

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BACKGROUND: Cardiovascular autonomic neuropathy (CAN) is a common complication of type 2 Diabetes mellitus (T2D), and prevalence varies according to the methodology used. CAN should be diagnosed in the subclinical stage when an intensive treatment of T2D could avoid the progression to irreversible phases. OBJECTIVE: Determine the prevalence of early involvement (EI) of CAN in T2D individuals comparing two methodologies. METHODS: This was a cross-sectional study that included 183 T2D individuals who were monitored in a Tertiary centre. The diagnosis of CAN was based on the results of four cardiovascular autonomic reflex tests (CARTs: expiration-inspiration index, Valsalva maneuver, orthostatic test, and changes in blood pressure after standing) and of seven heart rate variability (7HRV) indices (CARTs plus the spectral analysis). The findings were validated in an independent cohort comprised of 562 T2D individuals followed in a Primary care setting. RESULTS: With the use of 7HRV, 30.6% and 77.8% of individuals in the Tertiary and in the Primary centers, respectively, were classified as without CAN; 25.1% and 15.3% as EI and 44.3% and 6.9% as definitive CAN, respectively. The use of CARTs decreased the proportion of individuals without CAN in both centers (7.1% and 47%) and increased the frequency of EI (30.6% and 36.6%) and definitive CAN (62.3% and 16.4%), respectively. The concordance between both evaluated methodologies was weak. CONCLUSION: Higher proportions of T2D individuals were diagnosed with EI and with definitive CAN with the use of CARTs.

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Cardiovascular autonomic neuropathy (CAN) is a debilitating condition that mainly occurs in long-standing type 2 diabetes patients but can manifest earlier, even before diabetes is diagnosed. CAN is a microvascular complication that results from lesions of the sympathetic and parasympathetic nerve fibers, which innervate the heart and blood vessels and promote alterations in cardiovascular autonomic control. The entire mechanism is still not elucidated, but several aspects of the pathophysiology of CAN have already been described, such as the production of advanced glycation end products, reactive oxygen species, nuclear factor kappa B, and pro-inflammatory cytokines. This microvascular complication is an important risk factor for silent myocardial ischemia, chronic kidney disease, myocardial dysfunction, major cardiovascular events, cardiac arrhythmias, and sudden death. It has also been suggested that, compared to other traditional cardiovascular risk factors, CAN progression may have a greater impact on cardiovascular disease development. However, CAN might be subclinical for several years, and a late diagnosis increases the mortality risk. The duration of the transition period from the subclinical to clinical stage remains unknown, but the progression of CAN is associated with a poor prognosis. Several tests can be used for CAN diagnosis, such as heart rate variability (HRV), cardiovascular autonomic reflex tests, and myocardial scintigraphy. Currently, it has already been described that CAN could be detected even during the subclinical stage through a reduction in HRV, which is a non-invasive test with a lower operating cost. Therefore, considering that diabetes mellitus is a global epidemic and that diabetic neuropathy is the most common chronic complication of diabetes, the early identification and treatment of CAN could be a key point to mitigate the morbidity and mortality associated with this long-lasting condition.

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AIM: To evaluate the associations between HbA1c variability and long-term glycemic control with microvascular complications in type 1 diabetes (T1D) patients and multiethnic background. METHODS: T1D adults with ≥10 years of follow-up and ≥ 2 HbA1c measurements were included. Glycemic variability was evaluated by the standard deviation (HbA1c-SD), and coefficient of variation (HbA1c-CV), and glycemic control by mean HbA1c over 10 years. Diabetic retinopathy (DR), increased urinary albumin excretion rate (UAER) and reduced glomerular filtration rate (eGFR) were diagnosed. Cardiac autonomic neuropathy (CAN) was diagnosed by cardiac reflex tests. Associations between glycemic parameters with complications were assessed by multivariate logistic regressions. RESULTS: 220 patients were included. Simultaneously adjusted for each other, mean HbA1c was independently associated with DR (OR: 2.82; 95%CI: 1.45-5.50), increased UAER (OR: 1.97; 95%CI: 1.14-3.09) and CAN (OR: 4.42; 95%CI: 1.45-13.51); whereas HbA1c-CV was independently associated with DR (OR: 8.93; 95%CI: 1.86-42.87) and reduced eGFR (OR: 7.02; 95%CI: 1.47-35.55). CONCLUSIONS: Long-term glycemic control was associated with DR, increased UAER and CAN, while glycemic variability was additionally associated with DR and impaired renal function; suggesting that both good and stable glycemic status might be important to prevent microvascular complications in T1D patients and multiethnic background.

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En la diabetes mellitus(DM) el corazón es el órgano que se compromete con mayor frecuencia y lo hace a través de la enfermedad coronaria (EC), cardiopatía hipertensiva (CH), miocardiopatía diabética (MCDM) y neuropatía autónoma cardíaca (NAC), entidades de gran morbilidad y mortalidad y que pueden coexistir en el mismo paciente. Las personas diabéticas con enfermedad coronaria establecida son el grupo de mayor riesgo para presentar un infarto cardíaco. La EC en las personas diabéticas adquiere connotaciones propias en relación a su diagnóstico, evolución y tratamiento. En la DM por una parte está ampliamente reconocido el efecto nocivo de la hiperglicemia y de los factores de riesgo cardiovascular (FRCV) para la aparición y progresión de sus complicaciones y por otra, la evidencia de los grandes ensayos clínicos ha demostrado que un enfoque terapéutico global que incluya de manera temprana no sólo un estricto control de la glicemia sino que el resto de los FRCV trae consigo reducción de la morbilidad y mortalidad CV y general. Recientemente se ha estandarizado la manera de investigar y tratar estos factores en presencia de DM. La clave está en la pesquisa y tratamiento precoz de los estados de preDM y DM, y de los otros FRCV asociados como son la elevación del colesterol de LDL, de la presión arterial, eliminar el hábito de fumar y controlar la obesidad. Aunque aparentemente menos frecuentes pero no menos importantes son la MCDM y NAC, exigen una diagnóstico y tratamiento oportuno, al aumentar la morbimortalidad de causa cardiovascular. La insuficiencia cardíaca (IC) es frecuente en las personas con diabetes. La EC es la causa más frecuente de IC, pero la MCDM también contribuye y debe ser investigada ya que expone a mayor morbimortalidad, menor tolerancia al ejercicio y peor calidad de vida. La insuficiencia renal en etapa avanzada es causa frecuente de IC en DM. El objetivo de este artículo presentar una actualización del diagnóstico y manejo del compromiso cardiaco en la diabetes mellitus.

In diabetes mellitus (DM) the heart is the organ most frequently involved, being a major risk factor for developing coronary heart disease (CHD), hypertensive heart disease (HHD), diabetic cardiomyopathy (DCM) and cardiac autonomic neuropathy (CAN), entities with high morbidity and mortality,that can coexist in the same patient. Diabetics with established coronary heart disease have a major risk for acute myocardial infarction. Coronary Heart Disease in diabetics has its own features regarding diagnosis, prognosis and treatment. In DM it is widely recognized the deleterious effect of hyperglycemia as a cardiovascular risk factors (CVRF) for the onset and progression of complications. Moreover, the evidence from clinical trials has shown the importance of a global therapeutic approach, not only an early strict glycemia control, but also in the control at the rest CVRF, making possible to reduce CV morbidity and overall mortality. Recently it has been standardized the way to study and manage these factors, in the presence of DM. The key is, in the early research and treatment of pre-DM and DM states and the other associated cardiovascular risk factors, such as: high LDL cholesterol, blood pressure, smoking and obesity control. Although DCM and CAN are less frequent, they are not less important, requiring prompt diagnosis and treatment, because of its increased morbidity and mortality. Heart failure (HF) is common in people with diabetes. Although the CD is the most common cause of HF, is important to emphasize that DCM also contributes and should be investigated, because it increases morbidity and mortality, reduces exercise tolerance and worsens quality of life. The end-stage renal failure is a frequent cause of heart failure in diabetics. The aim of this article is to present an update of the diagnosis and management of the cardiac disease in diabetes mellitus.

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OBJECTIVES: This study evaluated plantar thermography sensitivity and specificity in diagnosing diabetic polyneuropathy using cardiac tests (heart rate variability) as a reference standard because autonomic small fibers are affected first by this disease. METHODS: Seventy-nine individuals between the ages of 19 and 79 years old (28 males) were evaluated and divided into three groups: control (n = 37), pre-diabetics (n = 13) and type 2 diabetics (n = 29). The plantar images were recorded at baseline and then minutes after a provocative maneuver (Cold Stress Test) using an infrared camera that is appropriate for clinical use. Two thermographic variables were studied: the thermal recovery index and the interdigital anisothermal technique. Heart rate variability was measured in a seven-test battery that included three spectral indexes (in the frequency domain) and four Ewing tests (the Valsalva maneuver, the orthostatic test, a deep breathing test, and the orthostatic hypotension test). Other classically recommended tests were applied, including electromyography (EMG), Michigan inventory, and a clinical interview that included a neurological physical examination. RESULTS: Among the diabetic patients, the interdigital anisothermal technique alone performed better than the thermal recovery index alone, with a better sensitivity (81.3%) and specificity (46.2%). For the pre-diabetic patients, the three tests performed equally well. None of the control subjects displayed abnormal interdigital anisothermal readouts or thermal recovery indices, which precluded the sensitivity estimation in this sample of subjects. However, the specificity (70.6%) was higher in this group. CONCLUSION: In this study, plantar thermography, which predominately considers the small and autonomic fibers that are commonly associated with a sub-clinical condition, proved useful in diagnosing diabetic neuropathy early. The interdigital anisothermal test, when used alone, performed best.

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